Estrogen Mediates Aurora-A Overexpression, Centrosome Amplification, Chromosomal Instability, and Breast Cancer in Female ACI Rats

• Published in: Proceedings of the National Academy of Sciences - PNAS 2004-12, Vol.101 (52), p.18123-18128
• Main Authors: Li, Jonathan J, Weroha, S John, Lingle, Wilma L, Papa, Dan, Salisbury, Jeffrey L, Li, Sara Antonia
• Format: Article
• Language: English
• Subjects: Aneuploidy; Animals; Aurora Kinase A; Aurora Kinases; Biological Sciences; Breast cancer; Breasts; Cell Cycle Proteins; Cells, Cultured; Centrosome - ultrastructure; Centrosomes; Chromosomes; Chromosomes - ultrastructure; Comparative genomic hybridization; DNA; DNA - metabolism; Drug therapy; Epithelial cells; Estrogens; Estrogens - metabolism; Female; Immunoprecipitation; Mammary Glands, Animal - pathology; Mammary Neoplasms, Animal - genetics; Mammary Neoplasms, Animal - metabolism; Mammary Neoplasms, Animal - pathology; Nucleic Acid Hybridization; Protein Kinases - biosynthesis; Protein Serine-Threonine Kinases; Rats; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - metabolism; Spleen - cytology; Time Factors; Tumors; Xenopus Proteins
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0408273101

Estrogens play a crucial role in the causation and development of sporadic human breast cancer (BC). Chromosomal instability (CIN) is a defining trait of early human ductal carcinoma in situ (DCIS) and is believed to precipitate breast oncogenesis. We reported earlier that 100% of female ACI (August/Copenhagen/Irish) rats treated with essentially physiological serum levels of 17β-estradiol lead to mammary gland tumors with histopathologic, cellular, molecular, and ploidy changes remarkably similar to those seen in human DCIS and invasive sporadic ductal BC. Aurora-A (Aur-A), a centrosome kinase, and centrosome amplification have been implicated in the origin of aneuploidy via CIN. After 4 mo of estradiol treatment, levels of Aur-A and centrosomal proteins, γ-tubulin and centrin, rose significantly in female ACI rat mammary glands and remained elevated in mammary tumors at 5-6 mo of estrogen treatment. Centrosome amplification was initially detected at 3 mo of treatment in focal dysplasias, before DCIS. At 5-6 mo, 90% of the mammary tumor centrosomes were amplified. Comparative genomic hybridization revealed nonrandom amplified chromosome regions in seven chromosomes with a frequency of 55-82% in 11 primary tumors each from individual rats. Thus, we report that estrogen is causally linked via estrogen receptor α to Aur-A overexpression, centrosome amplification, CIN, and aneuploidy leading to BC in susceptible mammary gland cells.